PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer | The NEW ENGLAND JOURNAL Of MEDICINE

Authors: Andrea Cercek, M.D., Melissa Lumish, M.D. https://orcid.org/0000-0003-4173-5567, Jenna Sinopoli, N.P., Jill Weiss, B.A., Jinru Shia, M.D., MichelleLamendola-Essel, D.H.Sc., Imane H. El Dika, M.D., and Luis A. Diaz, Jr., M.D.

BACKGROUND

Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer.

METHODS

We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.
PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer

RESULTS

A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.

CONCLUSIONS

Mismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.)
Locally advanced rectal cancer is typically managed with multimodal therapy, including chemotherapy, radiation, and surgery. Current evidence supports a strategy involving the use of neoadjuvant therapy, in which induction chemotherapy with a fluoropyrimidine in combination with oxaliplatin is followed by chemoradiotherapy and then surgery.1-3 This approach results in a pathological complete response in up to a quarter of patients, but it is associated with marked complications and toxic effects — including bowel, urinary, and sexual dysfunction; infertility; and altered quality of life — in a substantial proportion of patients.4-6 In patients undergoing surgery, resection of the rectum is life-altering and often warrants a permanent diverting colostomy.6,7 Owing to the complications of surgery and the high frequency of pathological complete response, interest in organ-sparing nonoperative management is increasing. The use of clinical complete response that is achieved with neoadjuvant treatment as a surrogate for pathological complete response provides patients with a nonoperative option that results in a survival benefit that is similar to that in patients undergoing surgical resection.8-11
Approximately 5 to 10% of rectal adenocarcinomas are mismatch-repair deficient, and these tumors have been shown to respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy in locally advanced rectal cancer.12-14 Immune checkpoint blockade alone has been shown to be highly effective as first-line treatment for patients with mismatch repair–deficient metastatic colorectal cancer, as well as for patients with treatment-refractory disease, with objective response rates of 33 to 55%, clinically significant durability of response, and prolonged overall survival.15-17
On the basis of the benefits seen in the context of metastatic disease, we hypothesized that single-agent programmed death 1 (PD-1) blockade alone might be beneficial in mismatch repair–deficient, locally advanced rectal cancer. To test this hypothesis, we initiated a phase 2 study to investigate the overall response and frequency of sustained clinical complete response to neoadjuvant treatment with dostarlimab, a PD-1 inhibitor, in this patient population.

Skip The Scoop | Seek Understanding

Bannon’s War Room | Evening Edition | Recorded July 7, 2021 | Video: 48 Minutes 58 Seconds

Show Me

New CPS program puts free condoms in nearly every school — including elementaries

Show Me

Loudoun County Schools Continue Fight Against Teacher Suspended for Objecting to Transgender Policy

Show Me

Woman says a person ‘with a beard and a penis’ got into hot tub with her daughter, 6, at LA spa

Show Me

State Department Will Let People Choose Their Gender on Passports

Show Me

Protest Erupts Following Alleged Penis Exposure By Transgender Woman At Spa

Show Me

VIDEOS: Violence Erupts As Antifa Beat Protesters At Wi Spa, Where Trans Woman Allegedly Showed Penis To Minors

Show Me

Biden’s Deputies Urge Children to Demand Transgender Status

Show Me

13-year-old transgender girl sues Florida Gov. Ron DeSantis over sports ban

Show Me

Illinois legislature passes law requiring feminine hygiene products in boys’ bathrooms

Show Me

‘Honestly it’s disgusting’: Fmr Olympic champ Caitlyn Jenner blasts ungrateful Gwen Berry

Show Me

Tolkien Society Goes Woke, ‘Finds’ Transgenderism, ‘Antiracism,’ and Queer-ness in The Lord of The Rings

Show Me

Camille Paglia – Lesson from History: Transgender Mania is Sign of Cultural Collapse | Video: 7 Minutes 10 Seconds

Show Me

13-year-old transgender soccer player suing Gov. DeSantis

Show Me

Tory Govt Placing Trans Women in Female Only Prisons Is Lawful, UK High Court Rules

Show Me

VIDEO: NFL Proudly Declares That ‘Football is Gay,’ ‘Queer,’ and ‘Transgender’

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded July 6, 2021 | Video: 48 Minutes 30 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded July 6, 2021 | Video: 48 Minutes 33 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded July 6, 2021 | Video: 42 Minutes 07 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 1 | Recorded July 5, 2021 | Video: 48 Minutes 35 Seconds

Show Me

Bannon’s War Room | Morning Edition Hour 2 | Recorded July 5, 2021 | Video: 48 Minutes 31 Seconds

Show Me

Bannon’s War Room | Evening Edition | Recorded July 5, 2021 | Video: 48 Minutes 59 Seconds

Show Me

Benjamin Franklin | Author Of The Declaration Of Independence | Video: 46 Minutes 37 Seconds

Show Me

“Woke” Hypocrites at Google Flash Gay Logo in US on YouTube During Pride Month but NOT in Turkey and China

Show Me

Filipino-American becomes the FIRST transgender woman to be crowned Miss Nevada

Show Me

In the UK, Resistance to Transgender Activism Is Fueled by Socialized Medicine and Feminist Wine Moms

Show Me

Advocates for Female Inmates Push Back as Transgender Prisoner Transfers Ramp Up in California

Show Me

In win for transgender student, Supreme Court refuses to hear case on bathroom ban

Show Me

Biological Male Barred From Women’s 400-Meter Olympic Hurdle Due to High Testosterone Levels

Show Me

Cuomo Signs Law Allowing Trans People To Amend Birth Certificates

Show Me

Kamala Harris: ‘My Pronouns Are She and Her’

Show Me

Police Arrest 2 Parents Who Spoke Out Against CRT, Transgenderism at Loudoun School Board Meeting

Show Me

Ex-New Zealand Olympic weightlifter weighs in on transgender athletes and Laurel Hubbard

Show Me

Japanese soccer player Kumi Yokoyama comes out as transgender

Show Me

Brett Favre Says It’s ‘Unfair’ For Laurel Hubbard And Transgender Women To Compete Against Biological Women

Show Me

Transgender Weightlifter to Compete in Olympics

Show Me

Transgender Olympian Said She Would Burn U.S. Flag on Podium if She Won

Show Me

“They’ve called me lots of things. Hitler, that was one. The fact that it has to do with transgender people is virtually irrelevant. The issue is compelled speech.” | Jordan Peterson | Video: 7 Minutes 18 Seconds

Show Me

Transgender student to receive $300K in discrimination suit

Show Me

Pediatrician Transgender Ideology Causing Child Abuse | President Of The American College Of Pediatricians

Show Me